Cardiovascular disease is the leading cause of morbidity and mortality in Westernized populations. Thus, the role of dietary micronutrients in decreasing LDL oxidation assumes considerable significance. The most consistent data with respect to micronutrient antioxidants and atherosclerosis appears to relate to alpha-tocopherol (AT), the predominant lipid-soluble antioxidant in LDL. In addition to decreasing LDL oxidation, data support an effect of ET on critical cells in atherogenesis (monocytes, smooth muscle cells and endothelium) that are potentially anti-atherogenic. The primary aim of the present proposal is to test the effect of AT supplementation (1200 IU/day of RRR-AT) in a placebo-controlled, randomized double blind trial over 2 years on the progression of carotid atherosclerosis in patients with coronary artery disease (stable angina pectoris or previous myocardial infarction). Subjects (n=120) recruited would have to be on the American Heart Association Phase II diet and a HMG CoA reductase inhibitor for at least one year and have an LDL cholesterol ,125 mg/dL on 2 visits at least 4 weeks part during the 10 month lead in phase. Intimal-medial thickness (IMT) of both carotids, including the common carotid, the bulb and the proximal internal carotid will be determined by high resolution B-mode sonography. At six month intervals blood samples will be obtained for liver enzymes, creatinine, complete blood count, lipid profile, antioxidant and fatty acid levels, LDL oxidation, plasma soluble CAMs (cell adhesion molecules) and monocyte activity. Also, an early morning urine sample will be obtained for F2-isoprostanes, a direct measure of lipid peroxidation. IMT will be determined at baseline, 1, 1.5 and 2 years. The mean change in IMT and rate of progression will be compared between the AT and placebo groups. Following isolation, the LDL will be subjected to copper catalyzed oxidation over a 5-hour period. From this will be obtained the lag phase and oxidation rate. Isolated monocytes will be activated with lipopolysaccharide and the following activities assayed: superoxide anion release, interleukin-1beta release and adhesion to human endothelium. F2 isoprostanes and VAM, ICAM, and E-& P-selectin will be quantitated by ELISA. AT levels and the parameters of LDL oxidation and monocyte activity will be correlated with changes in IMT. If this study show that high-dose AT supplementation is beneficial in retarding atherosclerosis this could emerge as an important adjunctive therapy in the management of cardiovascular disease.